Pharmaceutical compositions containing certain 3-nitro-furyl-4-azolidinylidene-azolones-5 and method of use

ABSTRACT

WHERE R4 and R5 are each straight or branched alkyl of 1 to 4 carbon atoms, or, together with each other and the nitrogen atom to which they are attached, morpholino, pyrrolidino, piperidino or N&#39;&#39;-methyl-piperazino, R2 is hydrogen or alkyl of 1 to 3 carbon atoms, R3 is hydrogen, straight or branched alkyl of 1 to 5 carbon atoms, or monohydroxy-(alkyl of 1 to 5 carbon atoms), X is oxygen, imino(-NH-) or methylimino(-NCH3-), Y is oxygen, sulfur or imino, and N IS 0 OR 1, OR, TO THE EXTENT THAT THE COMPOUNDS CONTAIN ONE OR MORE BASIC NITROGEN ATOMS, NON-TOXIC ACID ADDITION SALTS THEREOF; AND METHODS OF USING THE COMPOSITIONS AS BACTERICIDAL PREPARATIONS AGAINST GRAMPOSITIVE AND GRAMNEGATIVE BACTERIA AND AGAINST TRICHOMONAS.   WHEREIN R1 is hydrogen, straight or branched alkyl of 1 to 6 carbon atoms, monohydroxy-(alkyl of 1 to 6 carbon atoms), or   Pharmaceutical compositions containing as active ingredients compounds of the formula

United States Patent [191 Maier et al.

[ Feb. 26, 1974 PHARMACEUTICAL COMPOSITIONS CONTAINING CERTAIN 3-NITRO-FURYL-4-AZOLIDINYLIDENE- AZOLONES-S AND METHOD OF USE [75] Inventors: Roland Maier, Biberach/Riss;

Robert Sauter, Laupheim, both of Germany [73] Assignee: Boehringer Ingelheim GmbH,

lngelheim/Rhine, Germany 22 Filed: Dec. 29, 1972 211 App]. No.: 319,481

Related U.S. Application Data [62] Division of Ser. No. 177,435, Sept. 2, 1971, Pat. No.

[30] Foreign Application Priority Data Sept. 11, 1970 Germany 2045049 June 4, 1971 Germany 2127735 [52] U.S. Cl 424/270, 424/246, 424/248, 424/250, 424/267, 424/272, 424/273, 424/274 [51] Int. Cl A61k 27/00 [58] Field of Search... 424/246, 248, 250, 267, 270, 424/272, 273, 274

[56] References Cited.

UNITED STATES PATENTS 2,394,068 2/1946 Kendall et al 260/310 Primary Examiner-Jerome D. Goldberg Attorney, Agent, or Firm-Hammond & Littell [57] ABSTRACT Pharmaceutical compositions containing as active ingredients compounds of the formula RiH wherein R is hydrogen, straight or branched alkyl of 1 to 6 carbon atoms, monohydroxy-(alkyl of 1 to 6 carbon atoms), or

or, to the extent that the compounds contain one or more basic nitrogen atoms, non-toxic acid addition salts thereof; and methods of using the compositions as bactericidal preparations against grampositive and gramnegative bacteria and against trichomonas.

11 Claims, N0 Drawings PHARMACEUTICAL COMPOSITIONS CONTAINING CERTAIN 3-NITRO-FURYL-4-AZOLIDINYLIDENE- .AZ AND METHOD OF USE olNl J? R8 R: H

wherein R, is hydrogen, straight or branched alkyl of 1 to 6 carbon atoms, monohydroxy-(alkyl of 1 to 6 carbon atoms), or

where R, and R are each straight or branched alkyl of l to 4 carbon atoms, or, together with each other and the nitrogen atom to which they are attached, morpholino, pyrrolidino, piperidino or N'-methyl-piperazino,

R is hydrogen or alkyl of l to 3 carbon atoms,

R is hydrogen, straight or branched alkyl of l to 5 carbon atoms, or monohydroxy-(alkyl of l to 5 carbon atoms),

X is oxygen, imino(-NH-) or methylimino(-NC- Y is oxygen, sulfur or imino, and

n is 0 or 1, or, to the extent that the compound contains one or more basic nitrogen atoms, a non-toxic, pharmacologically acceptable acid addition salt thereof.

The compounds embraced by formula I above may be prepared by a number of different methods involving well known chemical principles, among which the following method has proved to be particularly convenient and efficient:

By reacting a compound of the formula wherein X has the same meanings as in formula I, and

R and R are each alkyl or, together with each other,

alkylene, with an amine of the formula III) wherein R R R Y and n have the same meanings as in formula 1.

The reaction is preferably carried out in the presence of an inert organic solvent or suspension medium at a temperature between 20 and 150 C. Examples of particularly suitable solvent and suspension media are polar organic liquids, such as alkanols, dioxane, alkanones, dimethylformamide or dimethylsulfoxide.

The intermediate compound formed by the reaction, of the formula wherein R R R X, Y and n have the same meanings as in formula I and R, has the same meaning as in formula II, may optionally be isolated and subsequently converted into the corresponding compound of the formula I, for instance, by heating to a temperature between and 200 C in the presence of a polar organic solvent, such as dimethylsulfoxide.

In those instances where the above-described method yields a compound of the formula I which comprises one or more basic nitrogen atoms, the basic compound may, if desired, be converted into an acid addition salt thereof by conventional procedures. Examples of nontoxic, pharmacologically acceptable acid addition salts are those formed with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, tartaric acid, citric acid, fumaric acid, 8-chlorotheophylline or the like.

The starting compounds of the formula II may be prepared by nitrating a compound of the formula wherein X, R,, and R have the meanings previously defined.

A compound of the formula V wherein R and R, are alkyl, in turn, may be prepared by reacting a furan derivative of the formula wherein X has the meanings previously defined, with carbon disulfide in the presence of a strong base, followed by alkylation of the dithio compound formed thereby.

Finally, those compounds of the formula V wherein R, and R together form an alkylene chain linking the two sulfur atoms may be prepared by subjecting a compound of the formula VI to a condensation reaction with a trithioearboxonium salt of the formula wherein R is alkyl, A is alkylene, and Z is an anion.

' The trithiocarboxonium salts of the formula VII, in turn, are accessible by alkylation of a cyclic trithiocarbonate with a dialkylsulfate, for example.

The following examples further illustrate the preparation of compounds of the formula I as well as a few starting compounds of the formulas 11 and [11. Preparation of Starting Materials EXAMPLE A 3-( Furyl-Z )-4-[ bis-methylmercapto )-methylene]- isoxazolone-S 7.9 gm (0.18 mol) of 55 percent sodium hydride were deoiled by decantation with petroleum ether and then suspended in 100 cc of dimethylsulfoxide. While exteriorly cooling the suspension with ice, a solution of 13.5 gm (0.09 mol) of 3-(furyl-2')-isoxazolone-5 and 6.9 gm (0.09 mol) of carbon disulfide in 50 cc of dimethylsulfoxide was slowly added dropwise thereto, and then the mixture was stirred for 30 minutes. Thereafter, while thoroughly cooling, 25.6 gm (0.18 mol) of methyl iodide were added dropwise, and then the resulting mixture was heated for 30 minutes at 50-60 C. Subsequently, after cooling, the reaction mixture was poured over ice, and the aqueous mixture was extracted with ethyl acetate. The organic phase was dried over sodium sulfate, and the ethyl acetate was evaporated, leaving a red oil which crystallized upon addition of a little ether. 12 gm (53 percent of theory) of yellow crystalline 3-(furyl-2')-4-[(bismethylmercapto)-methylenel-isoxazolone-S, m.p. 86 C, of the formula were obtained.

Using an analogous procedure, the following additional starting compounds of the formula V were prepared:

a. 3-( Furyl-Z )-4-[ (bis-methylmercapto methylene]-pyrazolone-5, a red crystalline substance, m.p. 148 C, of the formula from 3-(furyl-2' )-pyrazolone-5.

b. 3-(Furyl-2)-4-[(bis-methylmercapto)- methylene]-l-methyl-pyrazolone-S, a yellow crystalline substance, m.p. 83 C, from 3-(furyl-2')-1- methyl-pyrazolone-5 (m.p. 193 C); the latter, in turn, was prepared from ethyl furoylacetate and N- methyl-hydrazine.

EXAMPLE B 3-(Furyl-2' )-4-[ 1",3' -dithiacyclopentanylidene2" isoxazolone-S 12.1 gm (0.08 mol) of 3-(furyl-2)-isoxazolone-5 and 42 gm (0.16 mol) of 2-methylmercapto-1,3- dithiolaniummethylsulfate (prepared by heating a mixture of equimolar amounts of ethylene trithiocarbonate and dimethylsulfate on a water bath) were dissolved in 100 cc of pyridine, a solution of 16.2 gm (0.16 mol) of triethylamine in 100 cc of pyridine was added, and the mixed solution was heated for 3 hours at 70 C. Thereafter, the pyridine was drawn off in vacuo, the residue was admixed with water, and the crystalline substance formed thereby was collected by vacuum filtration and recrystallized from ethanol. 8.6 gm (42.3 percent of theory) of the faintly yellow crystalline compound, m.p. 160-162 C, of the formula were obtained. Analysis: c oH Nog 8;; mol. Wt. Calculated: C-47.4l%; H-2.78%; N-5.53%; S-25.32%

Found: 047.40%; H-2.94%; N-5.51%', S-25.05%

a. Using an analogous procedure, 3-(furyl-2)-4-[3"- methyl-thiazolidinylidene-2 ]-isoxazolone-5 m .p. 128 C (from isopropanol), was prepared from 3-(furyl-2')-isoxazolone-5 and 3-methyl-2-methylmercapto-thiazolidinium-methosulfate; the latter was, in turn, prepared from 2-methylmercapto-A2- thiazoline and dimethylsulfate.

EXAMPLE C 3-(5 Nitro-furyl-2' )-4-[(bis-methylmercapto)- methylene ]-isoxazolone-5 2.55 gm (0.01 mol) of 3-(furyl-2')-4-[(bismethylmercapto)-methylene]-isoxazolone-5 were. dis- SCH:

tional starting compounds of the formula 11! were prepared:

Analysis: c,.,H,N 0,s mol. wt. 300.32

Calculated: C-40.00%; H-2.69%; N-9.33%; S 21 .35%

- Found: C-39.80%; H-2.76%; N-9.35%', S-2l.45%

Using an analogous procedure, the following addi- 5 tional starting compounds of the formula II were prepared:

. 3-(5-Nitro-furyl-2)-4-[1",3-

dithiacylclopentanylidene-2"]-isoxazolone-5, brown crystals, m.p. 188 C (from dimethylformamide/water), from 3-(fury1-2)-4-[1",3- dithiacyclopentanylidene-Z )-isoxazolone-5.

EXAMPLE D 3-Morpholino-2-hydroxy-n-propylamine A mixture consisting of 69.5 gm (0.29 mol) of 3- chloro-2-hydroxy-n-propyl-phthalimide (see Berichte Deutsch. Chem. Ges. 50, 280), 53.2 gm (0.61 mol) of morpholine and 170 cc of ethanol was heated at its boiling point for 6 hours. Thereafter, the ethanol was evaporated, the residue was boiled for three hours with 600 cc of aqueous 20 percent hydrochloric acid, the mixture was allowed to cool and was then vacuumfiltered, the filtrate was concentrated by evaporation to 150 cc, and the concentrate was made strongly alkaline with solid caustic alkali. The oil precipitated thereby was taken up in benzene, and the aqueous phase was extracted twice with benzene. The combined benzene phases were dried over sodium sulfate and then fractionally distilled in vacuo, yielding 17.2 gm of the oily compound, b.p. l46-l48 C at 12 mm Hg, of the formula Using an analogous procedure, the following addia. 3-Piperidino-2-hydroxy-n-propylamine, a colorless oil, b.p. l28-129 C at 12 mm Hg, from 3-chloro- Z-hydroxy-n-propyl-phthalimide and piperidine.

b. 3-Pyrro1idino-2-hydroxy-n-propylamine, a colorless oil, b.p. l20-l2l C at 12 mm Hg, from 3- chlore-2-hydroxy-n-propyl-phtha1imide and pyrrolidine.

c. 3-(N-methyl-piperazino)-2-hydroxy-npropylamine, an oil, b.p. l16-l 18 C at 0.2 mm Hg, from 3-chloro-Z-hydroxy-n-propyl-phthalimide and N-methyLpiperazine.

d. 3-(Di-n-butylamino)-2-hydroxy-n-propylamine, a

colorless oil, b.p. 101 C at 0.3 mm Hg, from 3- chloro-2-hydroxy-n-propyl-phthalimide and dimbutylamine.

e. 3-(Di-isopropylamino)-2-hydroxy-n-propylamine,

a colorless oil, b.p. C at 0.01 mm Hg, from 3- chloro-2-hydroxy-n-propyl-phthalimide and diisopropylamine.

Preparation of End Products EXAMPLE 1 3-( 5 '-Nitro-furyl-2 )-4-[oxazolidinylidene-2' isoxazolone-S A mixture consisting of 2 gm (0.0066 mol) of 3-(5- nitro-furyl-2 )-4-[ bis-methylmercapto )-methylene] isoxazolone-S, 0.41 gm (0.0066 mol) of ethanolamine and 30 cc of acetone was heated at its boiling point for 1 hour. Thereafter, the reaction mixture was allowed to cool, and the precipitate formed thereby was collected by vacuum filtration and washed several times with acetone. 1.4 gm (80 percent of theory) of the yellowishcrystalline compound, m.p. 263 C (decomp.), of the formula were obtained.

Analysis: C H N O mol. wt. 265.19

Calculated: C 45.25%; H 2.66%; N 15.87% Found: C 45.40% H 2.74%; N 15.70%

EXAMPLE 2 Using a procedure analogous to that described in Example l 3-(5 '-nitro-furyl-2' )-4-[imidazolidinylidene- 2"]-isoxazol0ne-5, m.p. 280 C (decomp.; recrystallized from dioxane), was prepared from 3-(5'-nitrofuryl-2 )-4- bismethylmercapto )-methylene isoxazolone-S and ethylenediamine.

EXAMPLE 3 Using a procedure analogous to that described in Example l, 3-(5 -nitro-furyl-2' )-4-[ l -([3-hydroxyethyl)-imidazolidinylidene-2' l-isoxazolone-S m.p. 226 C (decomp.), was prepared from 3-(5'-nitrofuryl-2)-4-[bis-methylmercapto)-methylene]- isoxazolone-S and N-(fl-hydroxy-ethyD- ethylenediamine.

EXAMPLE 4 Using a procedure analogous to that described in Example l 3-( 5 '-nitro-furyl-2 )-4-[ 3 -(B-hydroxyethyl)-oxazolidinylidene-2"]-isoxazolone-5, m.p. C (recrystallized from methanol), was prepared from 3-( 5 -nitro-furyl-2 )-4-[ (bis-methylmercapto methylene]-isoxazolone-5 and diethanolamine.

EXAMPLE oxazolidinylidene-Z"]-isoXazolone-5, m.p. 205 C (recrystallized from ethylacetate/acetone), was prepared from 3-( 5 '-nitro-furyl-2' )-4-[ bis-methylmercapto)- methylenel-isoxazolone-S and N-methylethanolamine.

EXAMPLE 7 Using a procedure analogous to that described in Example 3-(5-nitro-furyl-2')-4-[thiazolidinylidene- 2"1-isoxazolone-5, m.p. 210 C, was prepared from 3- (5'-nitrofuryl-2)-4-[(bis-methylmercapto-methylene]- isoxazolone-S and cysteamine.

EXAMPLE 8 Using a procedure analogous to that described in Example 1, 3-(5-nitro-furyl-2' )-4-[4",5"-dimethyloxazolidinylidene-2"]-isoXazolone-5, m.p. 251 C, was prepared from 3-( 5 '-nitro-furyl-2 )-4-[ (bismethylmercapto)-methylene]-isoxazolone-5 and 2-amino-3-hydroxy-n-butane.

EXAMPLE 9 Using a procedure analogous to that described in EX- ample l, 3-( 5 -nitro-furyl-2' )-4-[ 5 '-methyl-oxazolidinylidene- 2]-isoxazolone-5, m.p. 253 C, was prepared from 3- (5-nitro-furyl-2)-4-[(bis-methylmercapto)- methylene]-isoxazolone-5 and 1-amino-2-hydroxy-npropane.

EXAMPLE 10 Using a procedure analogous to that described in EX- ample 1, 3-(5'-nitro-furyl-2' )-4-[4 '-methyloxazolidinylidene2"]-isoxazolone-5, m.p. 280 C, was prepared from 3-( 5 -nitro-furyl-2' )-4-[(bismethylmercapto)-methylenel-isoxazolone-S and 2-amino-l-hydroxy-n-propane.

EXAMPLE 1 1 Using a procedure analogous to that described in Example 1, 3-(5-nitro-furyl-2' )-4-[ 1 ,3"-tetrahydrooxazolidinylidene-2"]-isoXazo1one-5, m.p. 273 C, was prepared from 3-(5 '-nitro-furyl-2' )-4-[(bismethylmercapto)-methylene]isoxazolone-S and 1-amino-3-hydroxym-propane.

EXAMPLE 12 Using a procedure analogous to that described in Example 1, 3-(5'-nitro-furyl-2')-4-[5"-hydroxymethyloxazolidinylidene-2"-isoxazolone-5, m.p. 225 C (decomp.), was prepared from 3-(5'-nitro-furyl-2')-4- [(bis-methylmercapto-methylene]-isoxazolone-5 and l-amino-2,3-dihydroxy-n-propane.

EXAMPLE 13 Using a procedure analogous to that described in EX- ample 1, 3-( 5-nitro-furyl-2 )-4-[ 5 '-isopropyloxazolidinylidene-2"]-isoxazolone-5, m.p. 185 C (recrystallized from ethanol), was prepared from 3-(5'- nitro-furyl-Z )-4-[ (bismethylmercapto )-methylene -isoXazo1one-5 and l-amino-2-hydroxy-3-methyl-nbutane.

EXAMPLE 14 Using a procedure analogous to that described in Example 1, 3-(5'-nitro-furyl-2)-4-[4"-methyl-5"-ethyloxazolidinylidene-2"l-isoxazolone-S, m.p. 230 C (recrystallized from dioxane), was prepared from 3-(5- nitro-furyl-Z )-4-[ bis-methylmercapto )-methylene isoxazolone-S and 2-amino-3-hydroXy-n-pentane.

EXAMPLE 15 Using a procedure analogous to that described in Example 1, 3-(5-nitro-furyl-2)-4-[5-isopropyl-4"- methyloxazolidinylidene-Z"]-isoxazolone-5, m.p. 204 C (recrystallized from ethanol/acetone), was prepared from 3-(5-nitrofuryl-2)-4-[(bismethylmercapto)- methylene]-isoxazolone-5 and 2-amino-3-hydroxy-4- methyl-n-pentane.

EXAMPLE 16 Using a procedure analogous to that described in Example 1, 3-(5-nitro-furyl-2')-4-[ 1 "-ethylimidazolidinylidene-Z"l-isoxazolone-S, m.p. 235 C (decomp.), was prepared from 3-(5-nitro-furyl-2)-4- [(bis-methylmercapto)-methylene]-isoxazolone-5 and N-ethyl-ethylene-diamine.

EXAMPLE 17 Using a procedure analogous to that described in EX- ample 1, 3-( 5 '-nitro-furyl-2 )-4-[ 3 -ethyloxazolidinylidene-2"]-isoxazolone-5, m.p. 166 C (recrystallized from ethanol), was prepared from 3-(5'- nitro-furyl-2 )-4-[ bismethylmercapto )-methylene isoxazolone-S and N-ethyl-ethanolamine.

EXAMPLE 18 Using a procedure analogous to that described in Example l, 3-(5 '-nitro-furyl-2' )-4- [hexahydropyrimidinylidene-2 -isoxazolone-5 m .p. 243 C (decomp.), was prepared from 3-(5'-nitrofuryl-2' )-4-[ bis-methyl-mercapto)-methylene]- isoxazolone-S and 1,3-diamino-n-propane.

EXAMPLE 19 Using a procedure analogous to that described in Example l, 3-( 5 '-nitro-furyl-2' )-4-[ 5 '-n-hexyloxazolidinylidene-2"]-isoXazolone-5, m.p. C (recrystallized from ethanol), was prepared from 3-(5'- nitro-furyl-2)-4-[(bismethylmercapto)-methylene]- isoxazolone-S and 1-amino-2-hydroXy-n-octane EXAMPLE 20 Using a procedure analogous to that described in Example 1 3-( 5 -nitro-furyl-2 )-4- 5 '-n-pentyloXazolidinylidene-2]-isoxazolone-5, m.p. C, was prepared from 3-( 5 -nitro-furyl-2 )-4-[ (bismethylmercapto)-methylene]-isoXazo1one-5 and 1-amino-Z-hydrOXy-n-heptane.

EXAMPLE 22 Using a procedure analogous to that described in Example l 3-( -nitrofuryl-2 )-4- [4 '-ethyloxazolidinylidene-2"]-isoxazolone-5, m.p. 246 C, was prepared from 3-( 5 '-nitro-furyl-2 )-4- bismethylmercapto)-methylene]-isoxazolone-5 and 2-amino- 1 -hydroxy-n-butane.

EXAMPLE 23 Using a procedure analogous to that described in Example 1, 3-(5-nitro-furyl-2')-4-[l-methylhexahydropyrimidinylidene-2"]-isoxazo1one-5, m.p. 225 C (decomp.), was prepared from 3-(5'-nitrofuryl-2 )-4-[ (bis-methylmercapto )-methylene]- v isoxazolone-S and N-methyl-1,3-diamino-n-propane.

EXAMPLE 24 Using a procedure analogous to that described in Example 1, 3-( 5 -nitro-furyl-2 )-4-[ 3 -(B-hydroxyethyl)-thiazolidinylidene-2"]-isoXazolone-5, m.p. 188 C (decomp.), was prepared from 3-(5-nitro-furyl-2')- 4-[ bis-methylmercapto )-methylene ]-isoxazolone-5 and N-(B-hydroxy-ethyl)-cysteamine.

EXAMPLE 25 Using a procedure analogous to that described in Example 1, 3'(5'-nitro-furyl-2)-4-[3"-(/3-hydroxy-npropyl )-5 '-methyl-oxazolidinylidene-2 ]-isoxazolone- 5, 130 C (recrystallized from isopropanol), was prepared from 3-(5'-nitro-furyl-2')-4-[(bismethylmercapto )-methylene]-isoxazolone-5 and di-(B- hydroxy-n-propyl)-amine.

EXAMPLE 26 Using a procedure analogous to that described in Example 1, 3-(5 -nitro-furyl-2)-4-[ 3 "-n-butyloxazolidinylidene-2"]-isoxazolone-5, m.p. 110 C (recrystallized from ethanol), was prepared from 3-(5'- nitro-furyl-Z)-4-[(bismethylmercapto)-methylene]- isoxazolone-S and N-n-butylethanolamine.

EXAMPLE 27 Using a procedure analogous to that described in Example 1, 3-(5 '-nitro-furyl-2)-4-[ 1 "-n-propylimidazolidinylidene-Z"]-isoxazolone-5, m.p. 200 C (recrystallized from dioxane), was prepared from 3- (5-nitro-furyl-2)-4-[(bis-methylmercapto)- methylene]-isoxazolone-5 and N-n-propyl-ethylenediaminet EXAMPLE 28 Using a procedure analogous to that described in Example 1, 3-( 5 '-nitro-furyl-2 )-4-[ 3 -(B-hydroxy-npropyl)-oxazolidinylidene-2"]-isoxazolone-5, m.p. 153 C (recrystallized from ethanol), was prepared from 3-( 5 -nitro-furyl-2 )-4-[ bis-methylmercapto)- methylene1-isoxazolone-5 and N-(B-hydroxy-npropyl)-ethanolamine.

EXAMPLE 29 Using a procedure analogous to that described in Example 1, 3-(5-nitro-furyl-2')-4-[3"-('y-hydroxy-npropyl )-oxazolidinylidene-2' ]-isoxazolone-5 m.p. C (recrystallized from ethanol), was prepared from 3-(5'-nitro-fury1-2') -4-[(bis-methylmercapto)- methylene]-isoxazolone-5 and N-(y-hydroxy-n propyl)-ethanolamine.

EXAMPLE 30 Using a procedure analogous to that described in Example l, 3-(5-nitro-furyl-2)-4-[3"-(}3-methyl-nbutyl)-oxazolidinylidene-2' ]-isoxazolone-5 m.p. 1 40 C (recrystallized from ethanol), was prepared from 3- (5 -nitro-furyl-2') -4-[ bis-methylmercapto methylene]-isoxazolone-5 and N-(B-methyl-n-butyhethanaolamine.

EXAMPLE 31 Using a procedure analogous to that described in Example 1 3-( 5 -nitro-furyl-2' )-4-[ 3 ',5 -dimethyloxazolidinylidene-2"]-is0Xazolone-5, m.p. 196 C, was prepared from 3-( 5 '-nitro-furyl-2 )-4-[ (bismethylmercapto-methylene]-isoxazolone5 and 1- methylamino-2-hydroxy-propane.

EXAMPLE 32 Using a procedure analogous to that described in Example l 3-( 5 -nitro-furyl-2' )-4-[ 3 -isopropyloxazolidinylidene-2"]-isoxazolone-5, m.p. 198 C, was prepared from 3-( 5 '-nitro-furyl-2 )-4-[ bismethylmercapto)-methylene]-isoxazolone-5 and N-iospropyl-ethanolamine.

EXAMPLE 33 Using a procedure analogous to that described in Example 1, 3-( 5 -nitro-furyl-2 )-4-[ imidazolidinylidene-2' isoxazolone-S, m.p. 275 C (decomp.; recrystalliggl from dioxane), was prepared from 3-(5-nitro-furyl- 2 )-4-[ 1 ",3"-dithiacyclopentanylidene-2" isoxazolone-S and ethylenediamine.

EXAMPLE 34 Using a procedure analogous to that described in Example l, 3-(5 -nitro-furyl-2 )-4-[5 '-methyloxazolidinylidene-Z"]-pyrazolone-5, m.p. 275 C (decomp.; recrystallized from ethanol), was prepared from 3-( 5 '-nitro-furyl-2 )-4-[ (bis-methylmercapto methylenel-pyrazolone-S and l-amino-2-hydroxy-npropane.

EXAMPLE 35 Using a procedure analogous to that described in Example l, 3-(5'-nitro-furyl-2)-4-[thiazolidinylidene- 2]-pyrazo1one-5, m.p. 287 C (recrystallized from dimethylfomamide), was prepared from 3-(5-nitrofuryl-2)-4-[(bis-methylmercapto)-methylene]- pyrazolone-S and cysteamine.

EXAMPLE 36 Using a procedure analogous to that described in Example 1, 3-( 5 -nitro-furyl-2' )-4- S -methyloxazolidinylidene-2 l -methyl-pyrazolone-5 m .p. 274-275 C (recrystallized from ethanol), was prepared from 3-( 5 '-nitro-furyl-2) -4-[ (bismethylmercapto )-methylene 1 -methyl-pyrazoloneand 1-amino-Z-hydroxy-n-propane.

EXAMPLE 37 3-(5'-Nitro-furyl-2)-4-[ 1 ",3"- tetrahydrooxazinylidene-2 l-isoxazolone-S a. 2.0 gm (0.0066 mol) of 3-(5'-nitro-furyl-2')-4- [(bis-methylmercapto )-methylene l-isoxazolone-S were suspended in 30 cc of ethanol, and 0.52 gm (0.007 mol) of 3-hydroxy-n-propylamine were added to the suspension. Everything gradually went into solution, accompanied by evolution of mercaptan. After minutes of standing the solution was evaporated, and the residue was recrystallized from ethanol, yielding 1.2 gm of 3-(5'-nitro-furyl-2')-4-[(methylmercapto) -(y-hydroxy-n-propylamino)-methylene]-isoxazolone- 5, m.p. 168 C.

b. A mixture of 0.3 gm of this compound and 3 cc of dimethylsulfoxide was heated at its boiling point for five minutes and then allowed to cool, and the precipitate formed thereby was collected by vacuum filtration and washed with ether. 150 mgm of the same compound as in Example 11, m.p. 275-280 C, were obtained.

EXAMPLE 38 MU E were obtained.

' Analysis: C H N O mol. wt. 322.3

Calculated: C 48.45%; H 4.38%; N 17.37%

Found: C 48,50%; H 4,43%; N 17.40%

Its hydrochloride, obtained by treating the free base with hydrochloric acid, had a melting point of 251-253 C.

It tartrate, obtained by treating the free base with tartaric acid, had a melting point of 160-l65 C.

EXAMPLE 39 Using a procedure analogous to that described in Example 38, 3-(5-nitro-furyl-2)-4-[5"-(diethylaminomethyl )-oxazolidinylidene-2 l-isoxazolone-S m.p. 204 C, was prepared from 3-(5-nitro-furyl-2')-4- [(bis-methylmercapto )-me thylene -isoxazolone-5 and 3-diethylamino-2-hydroxy-n-propylamine.

EXAMPLE 40 Using a procedure analogous to that described in Example 38, 3-(5 '-nitro-furyl-2' )-4-[ 5 '-(piperidinomethyl )-oxazolidinylidene-2 l-isoxazolone-S m.p. 194 C, was prepared from 3-(5'-nitro-furyl-2')-4- [(bis-methylmercapto)-methylene]-isoxazolone-5 and 3-piperidino-2-hydroxy-n-propylamine.

EXAMPLE 41 Using a procedure analogous to that described in Example 38, 3-(5'-nitro-furyl-2)-4-[5"-(pyrrolidinomethyl) -oxazolidinylidene-2"]-isoxazolone-5, m.p. 205 C, was prepared from 3-(5-nitro-furyl-2)-4- [(bis-methylmercapto)-methylene]-isoxazolone-5 and 3-pyrrolidino-2-hydroxy-n-propylamine.

EXAMPLE 42 Using a procedure analogous to that described in Example 38, 3-(5-nitro-furyl-2')-4-[5"-(N- methylpiperazino -methyl )-oxazolidinylidene-2 isoxazolone-S, m.p. 146 C, was prepared from 3-(5- nitro-furyl-2 )-4-[ bis-methylmercapto )-methylene isoxazolone-S and 3-(N'-methylpiperazino )-2-hydroxyn-propylamine.

EXAMPLE 43 Using a procedure analogous to that described in Example 38, 3-(5-nitro-furyl-2')-4-[5"-(morpholinomethyl )-oxazolidinylidene-2 l-isoxazolone-S m .p. 220 C, was prepared from 3-(5'-nitro-furyl-2' )-4- [(bis-methylmercapto)-methylene]-isoxazolone-5 and 3-morpholino-2-hydroxy-n-propylamine.

EXAMPLE 44 Using a procedure analogous to that described in Example 38, 3-(5'-nitro-furyl-2')-4-[5"-(di-nbutylaminomethyl )-oxazolidinylidene-2 isoxazolone-S, m.p. 142 C, was prepared from 3-(5'- nitro-furyl-2 )-4- bis-methylmercapto )-methylene isoxazolone-S and 3-(di-n-butylamino)-2-hydr0xy-npropylamine.

EXAMPLE 45 Using a procedure analogous to that described in Example 38, 3-(5-nitro-furyl-2)-4-[5"-(diisopropylaminomethyl )-oxazolidinylidene-2 isoxazolone-S, m.p. 183 C, was prepared from 3-(5'- nitro-furyl-2 )-4-[ bis-methylmercapto )-methylene isoxazolone-S and 3-(di-isopropy1amino)-2-hydroxy-npropylamine.

EXAMPLE 46 Using a procedure analogous to that described in Example 38, 3(5'-nitro-furyl-2')-4-[5-(diethylaminomethyl)-3-methyl-oxazolidinylidene-2"]-isoxazolone- 5, m.p. 96 C, was prepared from 3-(5-nitro-furyl-2)- 4-[(bis-methylmercapto)-methylenel-isoxazolone-S and 3-diethylamino-2-hydroxy-N-mcthyl-npropylamine.

EXAMPLE 47 Using a procedure analogous to that described in Example 38, 3-(5'-nitro-furyl-2')-4-[5"-(dimethylaminomethyl )-oxazolidinylidene-2 ]-isoxazo1one-5 m.p. 192 C, was prepared from 3-(5'-nitro-furyl-2')-4- 1 ,3 -dithiacyclopentanylidene )-2 ]-isoxazolone-5 and 3-dimethylamino2-hydroxy-n-propylamine.

The compounds embraced by formula I above and, if they contain a basic nitrogen atom, their non-toxic acid addition salts, have useful pharmacodynamic properties. More particularly, they exhibit antibacterial activities and are especially effective against grampositive and grarnnegative bacteria, such as Staphylococcus aureus and Escherichia coli, as well as against trichomonads, especially Trichomonas vaginalis.

For instance, the following specific compounds are effective against Staphylococcus aureus and Escherichia coli within concentration ranges as low as 0.6 20'y/ml and 0.16 20'y/ml, respectively:

A. 3-( 5 '-Nitro-furyl-2 )-4-[imidazolidinylidene-2 isoxazolone-S,

3-( 5 '-Nitro-furyl-2' )-4-[oxazolidinylidene-2' isoxazolone-S C. 3-( 5 '-Nitro-furyl-2' )-4-[3 -methyloxazolidinylidene-Z"]-isoxazolone-5, D. 3-(5-Nitro-furyl-2)-4-[thiazolidinylidene-2"]- isoxazolone-S, E. 3-( 5 -Nitro-furyl-2' )-4-[ 5 -methyloxazolidinylidene-2' l-isoxazolone-S F. 3-(5-Nitro-furyl-2')-4-[4"-methyloxazolidinylidene-2"]-isoxazolone-5,

oxazolidinylidene-Z"]-isoxazolone-5, 3-( 5'-Nitro-furyl-2)-4-[ l",3"- tetrahydrooxazinylidene-2"]-isoxazolone-5, and

methyl )-oxazolidinylidene-2 I-isoxazolone-S.

Compounds (8). (D), (E) and (F) are also very cft'cctivc against Trichomonas vaginalis at minimum inhibiting concentrations below 0.2'y/ml.

For pharmaceutical purposes the compounds according to the present invention are administered to warmblooded animals topically or perorally as active ingredients in customary pharmaceutical compositions, that is, compositions consisting essentially of an inert pharmaceutical carrier and an effective amount of the active ingredient, such as tablets, coated pills, capsules, wafers, powders, solutions, suspensions, emulsions, syrups, suppositories, vaginal tablets and the like. One effective peroral dosage unit of the compounds according to the present invention is from 0.l67 to 2.5 mgm/kg body weight, preferably 0.83 to 1.67 mgm/kg body weight.

For topical administration, the preferred concentration is about 1 percent by weight, based on the total weight of the composition.

The following examples illustrate a few pharmaceutical compositions comprising a compound of the present invention as an active ingredient and represent the best modes contemplated of putting the invention into practical use. The parts are parts by weight unless otherwise specified.

EXAMPLE 48 Tablets The tablet composition is compounded from the following ingredients:

Preparation The isoxazolone compound, the lactose and the potato starch are intimately admixed with each other, the mixture is moistened with an aqueous l percent solution of the polyvinylpyrrolidone, the moist mass is forced through a 1.5 mm-mesh screen, the resulting granulate is dried at 45 C and again passed through the screen, the dry granulate is admixed with the magnesium stearate, and the composition is compressed into 220 mgm-tablets in a conventional tablet making machine. Each tablet contains 100 mgm of the isoxazolone compound and is an oral dosage unit composition with efiective anti-bacterial action.

The same result is obtained when an equal amount of 15 3-(5'-nitro-furyl-2')-4-[5"-(dimethylamino-methyl)- oxazolidinylidene-2"]-isoxazolone-5 or a non-toxic acid addition salt thereof is substituted for 3-(5'-nitrofuryl-2' )-4-[3 -(B-hydroxy-ethyl)-oxazolidinylidene- 2 ]-isoxazolone-5. 2O

EXAMPLE 49 Coated pills The pill core composition is compounded from the following ingredients:

Parts 3-( 5'-Nit ro-t'uryl-2' )-4-( 3"-(fl-hydroxy-cthyl) -oxazoIidinylidene-2l-isoxazolone-S Lactose 30.0 (om starch 30.0 (lelutln 1,0 Cellulose, microcryntnlllnc Mt Magnesium atenrnte H) Total l20.0

Preparation The isoxazolone compound, the lactose and the corn starch are intimately admixed with each other, the mixture is moistened with an aqueous 12 percent solution of the gelatin, the moist mass is forced through a 1.5 mm-mesh screen, the resulting granulate is dried at C and again passed through a 1.0 mm-mesh screen, the dry granulate is admixed with the cellulose and the magnesium stearate, and the composition is compressed into 120 mgm-pill cores, which are subsequently coated with a thin shell consisting essentially of a mixture of sugar and talcum, and polished with beeswax. Each coated pill contains mgm of the isoxazolone compound and is an oral dosage unit composition 50 with effective anti-bacterial action.

EXAMPLE 50 Vaginal tablets The tablet composition is compounded from the fol- The isoxazolone compound, the sorbitol and the carboxymethyl cellulose are intimately admixed with each other, the mixutre is moistened with aqueous 50 perinto 1,000 mgm-tablets. Each tablet contains 100 mgm of the isoxazolone compound and is an intra-vaginal dosage unit composition with effective antitrichomonal action.

EXAMPLE 5 l Tincture The tincture is compounded from the following ingredients:

Parts 3-; 5 '-Nitro-furyl- Z )-4-[ 3 -([3-hydroxy-ethyl) -oxazolidinylidene-2"]-isoxazolone-5 l Polyethyleneglycol 400 99.0

Total 100.0

EXAMPLE 52 Lotion The suspension is compounded from the following ingredients:

Q Q' -Nitm-furyI-Z')-4-[3"-(l3-hydroxy-ethyl) -oxazolidinylidene-2"]-isoxaz0lone-5 Sorbitan monopalmitate (Span 40) Polyglycol ether (Cremophor 0) Cctyl stearyl alcohol (Lanette O) Spermoceti Decyl oleate Distilled water Total Preparation The ingredients, except the active substance and the water, are admixed with each other, and the mixture is melted, brought to 70 C, and then emulsified into the distilled water at the same temperature. The resulting aqueous emulsion is cooled to 40 C, and the finely milled isoxazolone compound is suspended therein with the aid of an immersion homogenizer. The finished composition is then cooled to room temperature. The resulting lotion, which must be thoroughly shaken before use, contains 1 percent by weight of the isoxazolone compound and is a topical composition with effective anti-bacterial action.

The same result is obtained when an equal amount of 3 -nitro-furyl-2 )-4- 5 dimethylaminomethyl)-oxazolidinylidene-2"l-isoxazolone-S or a nontoxic acid addition salt thereof is substituted for 3-(5'- nitro-furyl-2' )-4-[3 -(B-hydroxy-ethyl)- oxazolidinylidene-2 ]-isoxazolone-5.

An oral dosage unit composition comprising a compound of the instant invention may, in addition, contain one or more other active ingredients, such as a muscle-relaxant, as illustrated by the following example.

EXAMPLE 53 Coated pills The pill core composition is compounded from the following ingredients:

Parts 3-(5'-Nitro-furyl-2)-4-[3-(fi-hydroxy-ethyl) -oxazolidinylidene-Tfi-isoxazolonZS Papax rin Corn Starch 32.0 Gelatin 3.0 Cellulose, microcrystalline 9.0 Magnesium stearate 1.0

Total l20.0

The isoxazolone compound, the papaverine and the corn starch are intimately admixed with each other, the mixture is moistened with an aqueous 12 percent solution of the gelatin, the moist mass is forced through a 1.5 mm-mesh screen, the resulting granulate is dried at 45 C and again passed through a 1.0 mmmesh screen, the dry granulate is admixed with the cellulose and the magnesium stearate, and the composition is compressed into mgm-pill cores, which are subsequently coated with a thin shell consisting essentially of a mixture of sugar and talcum, and finally polished with beeswax. Each coated pill contains 50 mgm isoxazolone compound and 25 mgm of papaverine, and is an oral dosage unit composition with effective anti-bacterial and musclerelaxing actions.

The same result is obtained when an equal amount of 3-( 5 '-nitro-furyl-2 )-4-[5 '-dimethylamino-methyl oxazolidinylidene-2]-isoxazolone-5 or a non-toxic acid addition salt thereof is substituted for 3-(5 -mtrofuryl-2 )-4-[3 -(,B-hydroxy-ethyl)-oxazolidinylidene- 2 ]-isoxazolone-5.

Analogous results are obtained when any one of the other nitrofuran derivatives embraced by formula I, or a non-toxic acid addition salt thereof, is substituted for the particular isoxazolone compound in Examples 48 to 53. Likewise, the amount of active ingredient in these illustrative examples may be varied to achieve the dosage unit range set forth above, and the amounts and nature of the inert pharmaceutical carrier ingredients may be varied to meet particular requirements.

While the present invention has been illustrated with the aid of certain specific embodiments thereof, it will be readily apparent to others skilled in the art that the invention is not limited to these particular embodiments, and that various changes and modifications may be made without departing from the spirit of the invention or the scope of the appended claims.

We claim:

1. A bactericidal or trichomonacidal pharmaceutical dosage unit composition consisting essentially of an inert pharmaceutical carrier and an effective bactericidal or trichomonacidal amount of a compound of the formula it; n

wherein R, is hydrogen, alkyl of l to 6 carbon atoms, monohydroxy-(alkyl of 1 to 6 carbon atoms), or

where R, and R are each alkyl of l to 4 carbon atoms, or, together with each other and the nitrogen atom to which they are attached, morpholino, pyrrolidino, piperidino or N-methyl-piperazino,

R is hydrogen or alkyl of l to 3 carbon atoms,

R is hydrogen, alkyl of 1 to 5 carbon atoms, or

monohydroxy-(alkyl of l to 5 carbon atoms),

X is oxygen, imino or methylimino,

Y is oxygen, sulfur or imino, and

n is or 1, or, when R, is CH NR R as defined above, a non-toxic, pharmacologically acceptable acid addition salt thereof.

2. The composition of claim 1, wherein said compound is 3-(5'-nitro-furyl-2')-4-(imidazolidinylidene- 2")-isoxazolone-5.

3. The composition of claim 1, wherein said compound is 3-(5-nitro-furyl-2)-4-(oxazolidinylidene- 2' )-isoxazolone-5.

4. The composition of claim 1, wherein said compound is 3-(5-nitro-furyl-2')-4-(3"-methyloxazolidinylidene-2' )-isoxazolone-5.

5. The composition of claim 1, wherein said compound is 3-( 5 '-nitro-furyl-2 )-4-(thiazolidinylidene- 2")isoxazolone-5.

6. The composition of claim 1, wherein said compound is 3-( 5 '-nitro-furyl-2' )-4-( 5 -methyloxazolidinylidene-2")-isoxazolone-5.

7. The composition of claim 1, wherein said compound is 3-( 5 '-nitro-furyl-2' )-4-(4 -methyloxazolidinylidene-Z)-isoxazolone-5.

8. The composition of claim 1, wherein said comwherein R, is hydrogen, alkyl of l to 6 carbon atoms, monohydroxy-(alkyl of l to 6 carbon atoms), or

where R, and R are each alkyl of '1 to 4 carbon atoms, or, together with each other and the nitrogen atom to which they are attached, morpholino, pyrrolidino, piperidino or N-methyl-piperazino,

R is hydrogen or alkyl of 1 to 3 carbon atoms,

R is hydrogen, alkyl of 1 to 5 carbon atoms, or

monohydroxy-(alkyl of l to 5 carbon atoms),

X is oxygen, imino or methylimino,

Y is oxygen, sulfur or imino, and

n is O or 1, or, when R. is CH NR R as defined above, a non-toxic, pharmacologically acceptable acid addition salt thereof. 

2. The composition of claim 1, wherein said compound is 3-(5''-nitro-furyl-2'')-4-(imidazolidinylidene-2'''')-isoxazolone-5.
 3. The composition of claim 1, wherein said compound is 3-(5''-nitro-furyl-2'')-4-(oxazolidinylidene-2'''')-isoxazolone-5.
 4. The composition of claim 1, wherein said compound is 3-(5''-nitro-furyl-2'')-4-(3''''-methyl-oxazolidinylidene-2'''')-isoxazolone-5.
 5. The composition of claim 1, wherein said compound is 3-(5''-nitro-furyl-2'')-4-(thiazolidinylidene-2'''')-isoxazolone-5.
 6. The composition of claim 1, wherein said compound is 3-(5''-nitro-furyl-2'')-4-(5''''-methyl-oxazolidinylidene-2'''')-isoxazolone-5.
 7. The composition of claim 1, wherein said compound is 3-(5''-nitro-furyl-2'')-4-(4''''-methyl-oxazolidinylidene-2'''')-isoxazolone-5.
 8. The composition of claim 1, wherein said compound is 3-(5''-nitro-furyl-2'')-4-(3''''-( Beta -hydroxy-ethyl)-oxazolidinylidene-2'''')-isoxazolone-5.
 9. The composition of claim 1, wherein said compound is 3-(5''-nitro-furyl-2'')-4-(1'''',3''''-tetrahydrooxazinylidene-2'''')-isoxazolone-5.
 10. The composition of claim 1, wherein said compound is 3-(5''-nitro-furyl-2'')-4-(5''''-(dimethylamino-methyl)-oxazolidinylidene-2'''') -isoxazolone-5 or a non-toxic, pharmacologically acceptable acid addition salt thereof.
 11. The method of inhibiting the growth of grampositive and gramnegative bacteria or trichomonas in a warm-blooded animal, which comprises Topically or perorally administering to said animal an effective bactericidal or trichomonacidal amount of a compound of the formula 